1. Field of the Invention
The present invention related to a dihydropyridine .revreaction.pyridinium salt type of redox system for the site-specific or sustained delivery (or both) of a wide variety of drug species to the testes. More especially, this invention relates to the discovery that a biologically active compound coupled to a lipoidal carrier moiety comprising a dihydropyridine nucleus readily and easily penetrates the blood-testis barrier ("BTB") and attains increased levels of concentration in the testes; oxidation of the dihydropyridine carrier moiety in vivo to the ionic pyridinium salts prevents its elimination from the testes, while elimination from the general circulation is accelerated, and subsequent cleavage of the quaternary carrier/drug species at least in part results in sustained delivery of the drug in the testes, or otherwise provides significant and prolongedly sustained testicular-specific pharmacological activity, with attendant facile elimination of the carrier moiety.
2. Description of the Background Art
In my aforenoted copending application, the Ser. No. 379,316, now U.S. Pat. No. 4,479,932 detailed reference is made to the well established fact that the delivery of drug species to the brain is ofttimes seriously limited by transport and metabolism factors and, more specifically, by the functional barrier of the endothelial brain capillary wall deemed the blood-brain barrier, BBB. Site-specific delivery and sustained delivery of drugs to the brain are even more difficult, and to date no useful simple or generic techniques to achieve such phenomena are known to the art.
Accordingly, acutely serious need exists in this art for a truly effective generic but nonetheless flexible method for the site-specific, or sustained delivery, or both, of drug species to the brain, and a major object of the invention disclosed and claimed in my said '316 copending application is the provision of just such a generic method for the site-specific/sustained delivery of centrally acting drug species to the brain, by administering to a patient in need of such treatment an effective amount of the target drug species [D] tethered to a reduced, blood-brain barrier penetrating lipoidal form [D--DHC] of a dihydropyridine.revreaction.pyridinium salt type redox carrier. Oxidation of the dihydropyridine carrier moiety in vivo to the ionic pyridinium salt type drug/carrier entity [D--QC].sup.+ prevents elimination thereof from the brain, while elimination from the general circulation is accelerated, and subsequent cleavage of the quaternary carrier/drug species results in sustained delivery of the drug [D] in the brain and facile elimination of the carrier moiety [QC].sup.+.
Another object of said '316 invention is to provide for brain-specific drug delivery utilizing a dihydropyridine.revreaction.pyridinium salt carrier type redox system, which drug/carrier system is characterized by enhanced drug efficacy and decreased toxicity. Indeed, consistent therewith systemic toxicity is significantly reduced by accelerating the elimination of the drug/quaternary carrier system, and even central toxicity is reduced by providing a low level, sustained release of the active drug species in the brain.
In capsule summary, my '316 invention features a dihydropyridine.revreaction.pyridinium salt carrier redox system for the specific and sustained delivery of drug species to the brain according to the following Scheme 1: ##STR1## Consistent with the foregoing Scheme 1, any drug species [D] is coupled to a quaternary pyridinium salt carrier [QC].sup.+ and the prodrug [D--QC].sup.+ which results is then reduced chemically to the lipoidal dihydro pro-prodrug form [D--DHC]. Alternatively, the drug species [D] can be directly coupled to the dihydro carrier [DHC] in certain instances to yield said pro-prodrug form [D--DHC]. After administration of the [D--DHC] in vivo, it is rapidly distributed throughout the body, including the brain. The dihydro form [D--DHC] is then in situ oxidized (rate constant, k.sub.1) (by the NAD.revreaction.NADH coenzyme system) to the ideally inactive original [D--QC].sup.+ quaternary salt prodrug, which, because of its ionic, hydrophilic character, is rapidly eliminated from the general circulation of the body, while the blood-brain barrier prevents its elimination from the brain (k.sub.3 &gt;&gt;k.sub.2 ; k.sub.3 &gt;&gt;k.sub.7). Enzymatic cleavage of the [D--QC].sup.+ that is "locked" in the brain effects a sustained delivery of the drug species [D], followed by its normal elimination (k.sub.5), metabolism. A properly selected carrier [QC].sup.+ will also be rapidly eliminated from the brain (k.sub.6 &gt;&gt;k.sub.2). Because of the facile elimination of [D--QC].sup.+ from the general circulation, only minor amounts of drug are released in the body (k.sub.3 &gt;&gt;k.sub.4); [D] is released primarily in the brain (k.sub.4 &gt;k.sub.2). The overall result is a brain-specific, sustained release of the target drug species. Cf. Bodor et al, Science, 214, 1370 (1981); C&EN, 24 (Dec. 21, 1981).
The existence of a blood-testis barrier (BTB) by which some substances are prevented from being carried into the seminiferous tubules long has been suspected [P. P. H. Bruyn, R. C. Robertson and R. S. Farr, Anat. Rec., 108, 279 (1950); R. J. Goldacre and B. Sylven, Nature (London) 184, 63 (1959); R. J. Goldacre and B. Sylven, J. Cancer, 16, 306 (1962); T. S. Ro and H. Busch, Biochem. Biophys Acta (Amst) 108, 317 (1965)]. Some investigators have suggested a similarity between the BBB and the BTB [A. T. Cowie, A. K. Lascelles and J. C. Wallace, J. Physiol. (London), 171, 176 (1964); R. E. Mancini, O. Vilar, B. Alvarez and A. C. Seiguer, J. Histochem. Cytochem., 13, 376 (1965); M. Kormano, Acta Physiol. Scand., 71, 125 (1967); M. Kormano, Histochemic, g, 327 (1967)]. Don W. Fawcett, Lee V. Leak and Paul M. Heidger, Jr., J. Reprod. Fert. Suppl. 10, 105 (1970) have suggested that the permeability barrier is not in the testis capillary walls because these more closely resemble the capillaries of muscle than those involved in the BBB. M. Dym and Don W. Fawcett, Biology of Reproduction, 3, 308 (1970) concluded that the epithelioid contractile layer around the seminiferous tubules constitutes a significant permeability barrier augmented by an apparently more efficient barrier involving tight cell-to-cell junctions between sertoli cells that inhibits penetration of substances through the germinal epithelium. Despite such histological differences, pharmacokinetic studies [K. Okumura, I. P. Lee and R. L. Dixon, J. Pharmacol. Exp. Therap., 194, 89 (1975); I. P. Lee and R. L. Dixon, Environmental Health Perspectives, 24, 117 (1978)] have demonstrated that the functional BTB resembles the BBB in transport characteristics, both depending on lipid solubility and molecular size. Thus, delivery of drug species to the testes is often seriously limited by the blood-testis barrier. Site-specific delivery and sustained delivery of drugs to the testes are even more difficult. To date, no useful simple or generic techniques to achieve such results are known to the art. It is thus apparent that a serious need exists in this art for a method for the site-specific and/or sustained delivery of drug species to the testes to elicit the desired therapeutic, e.g. hormonal or tumor-inhibiting, response.